P368: A PHASE II STUDY OF INOTUZUMAB OZOGAMICIN FOR THE TREATMENT OF MEASURABLE RESIDUAL DISEASE-POSITIVE B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: J. Senapati, H. Kantarjian, N. Short, Y. Alvarado, J. Burger, N. Jain, M. Konopleva, F. Ravandi, C. DiNardo, L. Masarova, K. Sasaki, P. A. Thompson, A. Ferrajoli, J. O. Jacob, E. D. Mayor, A. M. Milton, C. Loiselle, R. S. Garris, E. J. Jabbour
Journal: HemaSphere (2022)

Background: Persistence or re-emergence of measurable residual disease (MRD) in B-cell acute lymphoblastic leukemia (B-ALL) is strongly associated with shorter relapse-free survival. Inotuzumab ozogamicin (INO) is an anti-CD22 antibody-drug conjugate with the potential to eradicate MRD in B-ALL. Aims: We aimed to evaluate the efficacy of INO in clearing MRD in patients (pts) with persistent or recurrent MRD positivity after treatment with conventional chemotherapy. Methods: This is a single arm phase II trial of pts with B-ALL in complete remission (CR) who did not achieve MRD negativity (MRD-ve) or had MRD-positive (MRD+ve) relapse after at least 3 months (mos) from the start of frontline therapy (i.e. CR1) or 1 month from the start of any salvage therapy (i.e. ≥ CR2). Eligibility was defined by MRD+ve at ≥ 0.01%. MRD-ve was defined as undetectable MRD by flow cytometry at a minimum sensitivity of 10-4 for Philadelphia (Ph) negative (Ph-) B-ALL and undetectable MRD by both flow and PCR at 10-4 for Ph positive (Ph+) B-ALL. INO was given at a dose of 0.6 mg/m2 on D1 and 0.3 mg/m2 on D8 of C1 and 0.3 mg/m2 on D1 and 8 of subsequent cycles (up to 6 total cycles, given every 21-28 days) along with ursodiol prophylaxis. Pts with Ph+ ALL received concomitant TKI, the choice of which was decided by the treating physician. Results: Between 11/2018 and 1/2022, 20 pts with MRD+ve B-ALL, with a median age of 40 years (range, 19-68) were treated. Twelve pts (60%) had Ph+ B-ALL, 11 of whom received concurrent ponatinib and 1 dasatinib. Eight pts were Ph- (including 3 Ph-like ALL). Fourteen pts (70%) were in CR1, and 6 pts (30%) were in ≥ CR2 (3 in CR2, 2 in CR3 and 1 in CR4). Eleven pts (55%) had received prior blinatumomab (blina) and 4 pts (20%) had prior stem cell transplantation (SCT). The median BCR-ABL1 level in Ph+ B-ALL was 0.58% (range, 0.001-17.5%) and median MRD level by flow cytometry in Ph- B-ALL was 0.2% (range, 0.05-1.24%). Twelve pts (60%) became MRD-ve (responders), 10 after cycle 1 and 2 after cycle 2. In the Ph+ group, 6 pts (50%) responded; another 3 pts attained MMR as best response. Six of 8 (75%) Ph- pts responded. The median number of cycles were 3 (range, 1-6). Seven of 9 pts (78%) without prior blina exposure became MRD-ve, compared with 5/11 (45%) pts with prior blina exposure (p=0.22). Patient disposition is shown in Fig. 1A. Amongst the 12 responders, 5 pts were consolidated with ASCT after a median of 3 cycles (range, 1-3) of INO, all in MRD-ve CR pre-ASCT. Three responders (25%) relapsed (including 1 relapse after ASCT). At a median follow-up of 17 mos, 15 pts (75%) are alive, 8 of whom are in continued MRD-ve CR. The estimated 18 mos RFS and OS were 63% and 73% respectively, for the whole group (Fig. 1B), and the 18 mos OS was 87% and 55% for responders and non-responders, respectively. Outcomes were similar between pts with Ph+ ALL vs. Ph- ALL, prior blina exposure vs. no prior exposure, and pts in CR1 vs. ≥ CR2. INO was overall well-tolerated with no grade 4 non-hematological toxicities. Grade 3 non-hematological toxicities included elevated transaminases in 1 pt and veno-occlusive disease in 1 pt without history of prior ASCT. Ten pts (50%) had grade 3-4 hematological toxicities (primarily neutropenia). Image:Summary/Conclusion: Low-dose, fractionated INO is a well-tolerated option for MRD eradication in Ph+ and Ph- B-ALL pts, including in those with prior blina exposure.